The purpose of this study is to examine effective methods of preventing the transmission of HIV from mother to child during pregnancy, labor, and delivery. This is one part of the three-part PROMISE study. This study will be conducted at resource-limited locations in Africa and other parts of the world where women typically receive a short course of highly active antiretroviral therapy (HAART) during pregnancy and where formula feeding (FF) is standard.

Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point

Maternal Health Component: Death [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: AIDS-defining illness [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Composite endpoint of progression to AIDS-defining illness, death, or a serious non-AIDS cardiovascular, hepatic, or renal event [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: HIV/AIDS-related events [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Cardiovascular or other metabolic events [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Other targeted medical conditions [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or death [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or World Health Organization (WHO) Clinical Stage 2 or 3 event [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Composite endpoint of any condition outlined in Appendix IV of the protocol or death [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Tuberculosis [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

Maternal Health Component: Toxicity, defined as Grade 3 or greater laboratory results or signs and symptoms and selected Grade 2 renal and hepatic laboratory results [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: Yes ]

Maternal Health Component: Viral resistance [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

Maternal Health Component: Self-reported adherence [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

Maternal Health Component: Quality of life [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

Maternal Health Component: Changes in plasma concentrations of inflammatory and thrombogenic markers [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

Maternal Health Component: Cost-effectiveness [ Time Frame: Measured at the end of the 5-year study period ] [ Designated as safety issue: No ]

For women, 200 mg orally (one single dose) at onset of labor; for infants with birth weight greater than or equal to 2,500 gm: 1.5 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or through the Week 6 study visit, whichever is later; for infants with a birth weight of 2,000 to 2, 499 gm: 1.0 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever is later; for infants with a birth weight of less than 2,000 gm: 2 mg/kg based on birth weight orally once a day beginning as soon as possible after birth through 3 weeks of age and 4 mg/kg based on weight at 3 weeks of age orally once a day beginning at 3 weeks of age through 42 days of age or through the Week 6 visit, whichever is later.

Other Name: NVP

Drug: Emtricitabine-tenofovir disoproxil fumarate (Truvada [TRV])

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

All infants in the antepartum part of the study will receive NVP each day through 42 days of age or until the Week 6 study visit, whichever is later, regardless of the mother's study arm assignment.

Drug: Nevirapine (NVP)

For women, 200 mg orally (one single dose) at onset of labor; for infants with birth weight greater than or equal to 2,500 gm: 1.5 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or through the Week 6 study visit, whichever is later; for infants with a birth weight of 2,000 to 2, 499 gm: 1.0 mL suspension orally once a day beginning as soon as possible after birth through 42 days of age or until the Week 6 study visit, whichever is later; for infants with a birth weight of less than 2,000 gm: 2 mg/kg based on birth weight orally once a day beginning as soon as possible after birth through 3 weeks of age and 4 mg/kg based on weight at 3 weeks of age orally once a day beginning at 3 weeks of age through 42 days of age or through the Week 6 visit, whichever is later.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

Confirmed HIV-1 infection, documented by the results of testing performed on two separate specimens at any time prior to study entry. More information on this criterion can be found in the protocol.

Currently pregnant and at greater than 14 weeks gestation based on clinical or other obstetrical measurements

CD4 count greater than or equal 350 cells/mm^3 or greater than or equal to the country-specific threshold for initiation of treatment, if that threshold is greater than 350 cells/mm^3 on a specimen obtained within 30 days prior to study entry

Results of HBV screening (hepatitis B surface antigen [HBsAg] testing) available from specimen obtained within 30 days prior to entry

Certain laboratory values from a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

Plans to deliver in the study-affiliated clinic or hospital

Has no plans to move outside of the study site area during the 24 months following delivery

Age of legal majority for the respective country and willing and able to provide written informed consent

Intends to formula feed

Antepartum Component Exclusion Criteria (Step 1):

Participation in PROMISE for a prior pregnancy

Ingestion of any ARV regimen with three or more drugs (regardless of duration) or more than 30 days of a single or dual ARV regimen during current pregnancy, according to self report or available medical records

Requires triple-ARV therapy (HAART) for own health based on local standard guidelines

WHO Stage 4 disease

Prior receipt of HAART for maternal treatment indications (e.g., CD4 count less than 350 cells/mm^3 or clinical indications); however, could have received prior ARVs for the sole purpose of PMTCT in previous pregnancies; prior PMTCT regimens could have included a triple-ARV regimen, ZDV, 3TC-ZDV, and/or single-dose NVP for PMTCT as well as use of a short dual-nucleoside reverse transcriptase inhibitor (NRTI) "tail" to reduce risk of NVP resistance

Current or history of tuberculosis (TB) disease (positive purified protein derivative [PPD] without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to study entry (refer to protocol for list of prohibited medications)

Fetus detected with serious congenital malformation (ultrasound not required to rule out this condition)

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) is not considered exclusionary)

Known to meet the local standard criteria for treatment of HBV. More information on this criterion can be found in the protocol.

Social or other circumstances that would hinder long-term follow-up, in the opinion of the site investigator

Currently incarcerated

Antepartum Component Inclusion Criteria (Step 2):

On Antepartum Step 1 Arm A (ZDV + single dose NVP + TRV tail); OR

On Antepartum Step 1 Arm B or C (maternal triple-ARV prophylaxis) and currently receiving triple-ARV prophylaxis but does not meet the criteria for switching to a second line regimen (has not failed HAART) and Step 3 entry; OR

On Step 1 Arm B or C (maternal triple-ARV prophylaxis) and not enrolled in the Maternal Health Component but remains in observational follow-up and is not currently receiving a triple-ARV regimen (stopped the regimen)

Reached an indication for triple-ARV therapy (HAART) for own health, as specified in protocol

Willing and able to initiate HAART

Antepartum Component Exclusion Criteria (Step 2):

No exclusion criteria for this step.

Antepartum Component Inclusion Criteria (Step 3):

On Step 1 Arm B or C or on Step 2

Met the criteria for switching to a second-line regimen (as specified in the protocol) while on a triple-ARV regimen

Willing and able to continue a triple-ARV regimen

Antepartum Component Exclusion Criteria (Step 3):

- Women on 1077FA Step 1 Arm B or C who were not enrolled in the Maternal Health Component but remain in observational follow-up and are not currently receiving a triple-ARV regimen

Maternal Health Component Inclusion Criteria (Step 1):

Randomized to triple-ARV prophylaxis as part of the Antepartum Component and has continued triple-ARV prophylaxis until the current randomization (7 to 12 days postpartum) without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days

Provided written informed consent

CD4 cell count greater than or equal to 350 cells/mm^3 or greater than or equal to the country-specific threshold for initiation of treatment, if that threshold is greater than 350 cells/mm^3, on specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

Certain laboratory values on a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

Intend to remain in current geographical area of residence for the duration of study

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to entry in Maternal Health Component

Social or other circumstances that would hinder long-term follow-up, as judged by the site investigator

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) is not considered exclusionary)

Requires triple-ARV therapy for own health (includes women who are on Step 2 of the Antepartum Component and women who are on Step 3 of the Antepartum Component who entered Step 3 for immunologic/clinical disease progression requiring a change in their triple-ARV regimen (HAART). More information on this criterion can be found in the protocol.

Maternal Health Component Inclusion Criteria (Step 2):

On Step 1 Arm B (discontinue the study triple-ARV regimen arm); OR

On Step 1 Arm A (triple-ARV regimen) and currently on the triple-ARV regimen but does not meet the criteria for switching to a second-line regimen and entry into Step 3

Reached an indication for triple-ARV treatment for her own health, as specified in the protocol

Willing and able to reinitiate or continue triple-ARV therapy

Maternal Health Component Exclusion Criteria (Step 2):

No exclusion criteria for this step.

Maternal Health Component Inclusion Criteria (Step 3):

On Step 1 Arm A or Step 2

Meets the criteria for switching to a second-line regimen as specified in protocol while on a triple-ARV regimen

Willing and able to continue an alternative triple-ARV regimen (HAART)

Maternal Health Component Exclusion Criteria (Step 3):

- On Step 1 Arm B

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01253538

Locations

India

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, India, 411001

South Africa

Soweto IMPAACT CRS

Johannesburg, Gauteng, South Africa, 1862

Durban Paediatric HIV CRS

Durban, KwaZulu-Natal, South Africa, 4001

Family Clinical Research Unit (FAM-CRU) CRS

Tygerberg, Western Cape Province, South Africa, 7505

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)